Process for preparing a 2(1-(2-amino-5-phenyl) - 1 - phenylmethylamino)acetic acid derivative



United States Patent 3,522,289 PROCESS FOR PREPARING A 2[1-(2-AMINO-5- PHENYL) 1 PHENYLMETHYLAMIN 01ACE- TIC ACID DERIVATIVE Giles Allan Archer, Essex Fells, and Leo Henryk Stembach, Upper Montclair, N.J., assignors to Hoffman- }.a Roche Inc., Nutley, N.J., a corporation of New ersey No Drawing. Original application June 15, 1964, Ser. No. 375,292, now Patent No. 3,370,091, dated Feb. 20, 1968. Divided and this application Apr. 21, 1967, Ser.

Int. Cl. C07c 103/22 US. Cl. 260-471 4 Claims ABSTRACT OF THE DISCLOSURE A process for preparing a 2[1 (2 amino 5-phenyl)- 1 phenylmethylamino]acetic acid derivative from a 2- arnino benzhydryl halide or Z-amino benzhydryl amine. This derivative is a useful intermediate in the preparation of l,3,4,5 tetrahydro 5 phenyl-ZH-1,4 benzodiazepin- 2-ones which are a known pharmaceutically useful class of compounds.

CROSS REFERENCES TO RELATED APPLICATIONS This application is a divisional application of Ser. No. 375,292, Archer et al., filed June 15, 1964, now US. Pat. No. 3,370,091, issued Feb. 20, 1968.

BACKGROUND OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION More particularly, the present invention comprehends a method for the preparation of compounds of the formula:

OBI-R4 wherein R and R are each selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, halogen, nitro, trifluoromethyl, lower alkyl and lower alkoxy; and R is selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro, cyano, lower alkyl-thio, lower 'alkyl-sulfinyl, lower alkyl-sulfonyl, lower alkyl and lower alkoxy;

3,522,289 Patented July 28, 1970 which comprises intramolecularly condensing a compound of the formula:

wherein R R R and R have the same meaning as above, and R is selected from the group consisting of lower alkoxy, hydroxy, aryloxy and amino.

As used herein, the term lower alkyl comprehends saturated straight and branched chain hydrocarbon groups, for example, methyl, ethyl, propyl, isopropyl and the like. The term halogen comprehends all four halogens, i.e. iodine, bromine, fluorine and chlorine (the latter three being preferred). The terms lower alkyl-thio, lower alkylsulfinyl, lower alkyl-sulfonyl and lower 'alkoxy comprehend moieties wherein the lower alkyl part is as defined for lower alkyl above, for example, methoxy, ethoxy, methyl-thio, methyl-sulfinyl, methyl-sulfonyl and the like. Amino comprehends unsubstituted and substituted amino groups such as --NH -NH(lower alkyl) and N (lower alkyl) Aryloxy comprehends aromatic cyclic hydrocar-bonoxy groups such as phenoxy and the like.

As stated above, one embodiment of this invention comprehends the preparation of compounds of Formula I via intramolecular condensation of compounds of Formula II. The cmpounds of Formula II, depending on the meaning of R are either aminoacetic acids, amino acetates (i.e. esters), or aminoacetamides. While the intramolecular condensation can be eiiected with any of these, it is preferred to effect the intramolecular condensation utilizing compounds of Formula II which are aminoacetic acids .(i.e. R is hydroxy). In such instances the intramolecular condensation constitutes a dehydration. The intramolecular condensation can suitably be effected by heating a compound of Formula II in an inert organic solvent. The dehydration embodiment (i.e. R is hydroxy) constitutes a specific exemplification of the intramolecular condensation. This dehydration can be effected by any suitable means but preferably is effected by heating in an inert organic solvent. This heating can be effected at temperatures from about 25 C. to about 300 C. but temperatures from about C. to about 200 C. are especially preferred. Exemplary of useful organic solvents are hydrocarbons, for example, aromatic hydrocarbons such as xylene and the like, halogen containing hydrocarbons such as methylene chloride and the like, ethers such as ether, diglyme, tetrahydrofuran and the like, and basic nitrogen containing heterocycles such as pyridine, piperidine or the like. Mixtures of inert organic solvents can also be used to advantage.

Compounds of Formula II which are Z-aminobenzhydrylaminoacetic acids are preferred starting materials for the abovedescribed process and can be prepared by a variety of methods. More particularly, they can be prepared by hydrolysis of corresponding esters or amides of the formula:

R1 Am wherein R R A and R have the same meaning as above and R is lower alkyloxy, amino or aryloxy. The compounds of Formula II (including those of Formula III) can be prepared via reaction of corresponding Z-aminobenzhydrylamincs with a lower alkyl or aryl haloacetate (bromo and chloroacetate are especially preferred), a halo-acetamide or a halo-acetic acid. This rewherein R R and R have the same meaning as above; via reaction with a glycine compound of the formula wherein R and R have the same meaning as above.

The benzhydryl halides of Formula IV can be prepared by treatment of corresponding benzhydrols with a halogenating agent (iodinating, chlorinating and brominating agents being preferred, chlorinating agents are especially preferred). As exemplary halogenating agents there can be named, thionyl halides such as thionyl chloride and thionyl bromide; phosphorus trihalides or pentahalides such as phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride; or hydrogen halides such as hydrogen chloride or hydrogen bromide; or the like. The so-formed benzhydryl halide can then be isolated (advantageously in the form of its acid addition salt, for example, as the acid addition salt formed during the halogenation reaction) or, preferably, is further reacted by adding the glycine compound of Formula V directly to the reaction mixture in which the benzhydryl halide of Formula IV has been formed. A preferred embodiment of the reaction with a benzhydryl halide of Formula IV constitutes using as the glycine compound of Formula V, a glycine ester (i.e. R is lower alkoxy or aryloxy).

The hydrolysis of the aminoacetate ester or aminoacetamide of Formula III to the acetic acid of Formula II is suitably efiected via either alkaline or acid hydrolysis and can be eflected at either room temperature or above or below room temperature. Preferably, it is effected at above room temperature by refluxing the ester of Formula III in either an acidic or basic aqueous medium.

The following examples are illustrative but not limitative of the invention. All temperatures are stated in C.

Example 1 2 amino 5 chlorobenzyhydrylamine dihydrochloride (30.6 gm.) was dissolved in water (150 1111.), and made basic with sodium hydroxide solution. Extraction of the mixture with methylene chloride gave 2-amino-5- chloro-benzhydrylamine as a pa e yellow viscous oil.

4 Example 2 Z-amino 5 chlorobenzhydrylamine (11.64 gm., 0.050 mol), dissolved in dry benzene ml.), was treated with triethylamine (7.2 ml., 10.1 gm., 0.100 mol). The reaction mixture was then stirred inan ice-bath at 0-5", during the dropwise addition (in the course of 2030 minutes) of a solution of ethyl bromoacetate (5.52 ml., 8.35 gm., 0.050 mol) in dry benzene (20 ml.). Stirring was then continued for 16 hours at room temperature, which was followed by refluxing the mixture on a steambath for one hour. After cooling, the reaction mixture was poured into water, and extracted with methylene chloride, to give a bright yellow oil. This was partitioned between dilute hydrochloric acid and ether; the aqueous acid layer was made basic With sodium hydroxide solution, and extracted with methylene chloride, to give the crude product as a viscous yellow gum. Trituration with hexane, followed by several recrystallizations from hexane, and from ethanol, gave 2-[1-(2-amino-5-chlorophenyl)-1-phenylmethy1amino]acetic acid ethyl ester as colorless rods, M.P. l03104 C.

Example 3 2 [1-(2-amino-5-chlorophenyl)-l-phenylmethylamino] acetic acid ethyl ester (1.81 gm.) was refluxed in a mixture of saturated methanolic barium hydroxide (30 ml., circa 1 N) and water (10 ml.) for 17 hours. The resulting precipitated barium salt was filtered ofl after cooling the mixture, and recrystallized from water, giving colorless needles (M.P. 206210). The barium salt was then dissolved in dimethylformamide (20 ml.), and converted to the free acid by addition of the calculated amount of 1 N-sulfuric acid, followed by filtration to remove the precipitated barium sulfate. Concentration of the filtrate, and dilution with water, gave 2[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino] acetic acid as pale yellow prisms (from methanol). The melting-point was rather indefinite, circa 234242 dec.

Example 4 A suspension of 2-[1-(2 amino 5 chlorophenyl)-lphenylmethylamino1acetic acid (1.00 gm.) in dry xylene (20 ml.) was stirred and refluxed for six hours; some solid material remained undissolved. The mixture was cooled and filtered, giving 7-chloro-1,3,4,5-tetrahydro-S-phenyl- 2H-l,4 benzodiazepin 2 one as colorless prisms, M.P. 181-185.

Example 5 A solution of 2[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino1acetic acid (1.00 gm.) in anhydrous pyridine (10 ml.) and piperidine (0.02 ml.) was refluxed for 17 hours. The mixture was evaporated in vacuo, and the residue was partitioned between diluted hydrochloric acid and ether. The aqueous acid layer was made basic with sodium hydroxide solution, and the resulting precipitate was filtered off and recrystallized from ethanol, giving 7-chloro-1,3,4,5-tetrahydro-5-pheny1 2H-1,4-benzodiazepin-2-one as colorless prisms, M.P. 183-185 C.

Example 6 Z-amino 5 chlorobenzhydrylamine dihydrochloride (30.6 gm., 0.100 mol), suspended in ethanol (200 ml.), was treated with anhydrous sodium carbonate (21.2 gm., 0.200 mol); the mixture was refluxed and treated dropwise (in the course of 1 hour) with a solution of ethyl bromoacetate (11.1 ml., 16.7 gm., 0.100 mol) in ethanol (25 ml.). Stirring and refluxing were continued for 24 hours, then the mixture was filtered, and the combined filtrates were concentrated in vacuo. The resulting residue was worked up in the manner described in Example 2 for the preparation of compound 2-[1-(2-arnino-5-chlorophenyl)- l-phenylmethylamino] acetic acid ethyl ester, giving a yellow oil. This was hydrolyzed by refluxing it with a mixture of aqueous 1 N-sodi-um hydroxide solution ml.) and ethanol (240 ml.) for 3 hours. The resulting solution was concentrated in vacuo, diluted with water, and acidified with 3 N-acetic acid (pH 6), to give creamcolored prisms containing 2[1-(2-amino-5-chlorophenyl)- l-phenylmethylamino] acetic acid. The so-obtained crude product was cyclized to 7-chloro-1,3,4,5-tetrahydro-5- phenyl-ZH-1,4-benzodiazepin-2-one by treatment with refluxing xylene, as described in Example 4 giving tancolored prisms, M.P. 182186 C.

Example 7 A solution of Z-amino-5-chlorobenzhydrol (23.4 gm., 0.100 mol) in ethylene dichloride (250 ml.) was stirred and treated with dry hydrogen chloride, which was bubbled through the mixture until excess was present. Then pyridine (2 drops) and thionyl chloride (14.4 ml., 23.8 gm., 0.200 mol) was added, and the mixture was refluxed until evolution of sulfur dioxide virtually ceased (0.5 hour). The mixture was then evaporated in vacuo, with protection from atmospheric moisture. The residue was dissolved in methylene chloride (200 ml.) and evaporated again to remove excess thionyl chloride. The residue so-obtained by evaportaion of the reaction mixture, was dissolved in methylene chloride (60 ml.). The solution was then stirred and cooled in an ice-bath, while a solution of freshly distilled glycine ethyl ester (10.3 gm., 100 millimoles) in methylene chloride (25 ml.), was added dropwise over the course of 30 minutes. The mixture was then stirred for 1 hour at room temperature, and poured into icewater. The organic layer was then evaporated giving the crude product as a brown, partly crystalline residue. This was partitioned between ether and dilute hydrochloride acid; the acid layer was made basic wtih sodium hydroxide solution, and extracted with methylene chloride, to give the almost pure product, 2-[1-(2-amino-5-chlorophenyl)- 1-phenylmethylamino]acetic acid ethyl ester, as a tancolored crystalline residue. One recrystallization from methylene chloride-hexane gave colorless prisms, M.P. 102105 C.

We claim:

1. A method for the preparation of compounds of the formula Rt 4m wherein R and R are each selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, halgen, nitro, trifiuoromethyl, lower alkyl and lower alkoxy; R is selected from the group consisting of hydrogen, halogen, trifiuoromethyl, nitro, cyano, lower alkylthio, lower alkyl-sulfinyl, lower alkyl-sulfonyl lower alkyl and lower alkoxy and R is selected from the group consisting of hydroxy, lower alkoxy, phenoxy and amino;

which comprises reacting a compound of the formula wherein R R and R have the same meaning as above, with a compound of the formula wherein R and R have the same meaning as above.

2. A method for the preparation of compounds of the formula wherein R and R are each selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, halogen, nitro, trifiuoromethyl, lower alkyl and lower alkoxy; R is selected from the group consisting of hydrogen, halogen, trifiuoromethyl, nitro, cyano, lower alkyl-thio, lower alkyl-sulfinyl, lower alkyl-sulfonyl lower alkyl and lower alkoxy and R is selected from the group consisting of hydroxy, lower alkoxy, phenoxy and amino;

which comprises reacting a compound of the formula 3 (EH-N112 wherein R R and R have the same meaning as above,

References Cited Karrer, P., Organic Chemistry (1950), pub. by Elsevier Publishing Co., Inc., New York, p. 453 relied on.

Fieser et 211., Organic Chemistry (1956), pub. by Reinhold Publishing Corp., New York, p. 342 relied on.

LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, Assistant Examiner US. Cl. X.R. 

